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Chembiochem. 2017 May 18;18(10):914-920. doi: 10.1002/cbic.201700052. Epub 2017 Apr 7.

Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors.

Author information

1
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL, 61801, USA.
2
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, 92093, USA.
3
Department of Chemistry, University of California, 1 Shields Avenue, Davis, CA, 95616, USA.
4
Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
5
Center for Biophysics and Computational Biology, 607 South Mathews Avenue, Urbana, IL, 61801, USA.
6
Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA, 92093, USA.
7
National Biomedical Computation Resource, University of California at San Diego, La Jolla, CA, 92093, USA.

Abstract

Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target is (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H+ /2e- reduction. IspH contains a 4 Fe-4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe-4 S clusters by η1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H2 O, O2 ) binding. Based on these ideas, we used in silico methods to find drug-like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a Ki value of ≈500 nm against Pseudomonas aeruginosa IspH.

KEYWORDS:

HYSCORE; IspH; NRVS; in silico; isoprenoid

PMID:
28253432
PMCID:
PMC5445010
DOI:
10.1002/cbic.201700052
[Indexed for MEDLINE]
Free PMC Article

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